D‐glyceric aciduria is caused by genetic deficiency of D‐glycerate kinase (GLYCTK)

D-glyceric aciduria is a rare inborn error of serine and fructose metabolism that was first described in 1974. Most affected individuals have presented with neurological symptoms. The molecular basis of D-glyceric aciduria is largely unknown; possible causes that have been discussed are deficiencies of D-glycerate dehydrogenase, triokinase, and D-glycerate kinase. In 1989, van Schaftingen has reported decreased D-glycerate kinase activity in the liver of a single patient with D-glyceric aciduria. However, this analysis has not been performed in other affected individuals, and the underlying defect has remained unknown on the gene level until now. We report three patients with deficiency of D-glycerate kinase. They are of Serbian, Mexican, and Turkish origin and include the patient initially reported in 1974. All had homozygous mutations in exon 5 of the GLYCTK gene encoding D-glycerate kinase: c.1448delT (p.Phe483SerfsX2), c.1478T>G (p.Phe493Cys), or c.1558delC (p.Leu520CysfsX108). Transient overexpression of the variant GLYCTK genes in HEK293 cells clearly showed loss of enzyme activity and immunoreactivity when compared to the reference enzyme. Our work has revealed mutations in the GLYCTK gene as the cause of D-glycerate kinase deficiency and D-glyceric aciduria and provides a noninvasive approach for further diagnostic workup and research. Hum Mutat 31:1–6, 2010. © 2010 Wiley-Liss, Inc.